DE69907509T2 - PPHOSPHOLIPID COMPLEXES OF PROANTHOCYANIDINE A2 AS ANTIATHEROSCLEROTIC AGENTS - Google Patents

PPHOSPHOLIPID COMPLEXES OF PROANTHOCYANIDINE A2 AS ANTIATHEROSCLEROTIC AGENTS Download PDF

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DE69907509T2
DE69907509T2 DE69907509T DE69907509T DE69907509T2 DE 69907509 T2 DE69907509 T2 DE 69907509T2 DE 69907509 T DE69907509 T DE 69907509T DE 69907509 T DE69907509 T DE 69907509T DE 69907509 T2 DE69907509 T2 DE 69907509T2
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proanthocyanidin
phospholipid
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phospholipids
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Ezio Bombardelli
Paolo Morazzoni
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
    • A61K31/685—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/543—Lipids, e.g. triglycerides; Polyamines, e.g. spermine or spermidine
    • A61K47/544—Phospholipids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Abstract

The present invention relates to complexes of proanthocyanidin A2 and one or more phospholipids, pharmaceutical compositions containing the complex of proanthocyanidin A2 and one or more phospholipids, and methods of treating or preventing atherosclerosis and myocardial and cerebral infarction in a patient by administering the complex of proanthocyanidin A2 and one or more phospholipids, as well as methods of forming such complexes

Description

Die vorliegende Erfindung bezieht sich auf Phospholipidkomplexe von Proanthocyanidin A2 und auf deren Verwendung zur Herstellung von Medikamenten zur Prophylaxe und Therapie von Atherosklerose und Myocard- und Hirninfarkt.The present invention relates on phospholipid complexes of proanthocyanidin A2 and on their Use in the manufacture of medicines for prophylaxis and therapy of atherosclerosis and myocardial and cerebral infarction.

Proanthocyanidin A2 oder 8,14-Methano-2H,14H-1-benzopyrano[7,8-d][1,3]benzodioxocin-3,5,11,13,15-pentol-2,8-bis-(3,4-dihydroxyphenyl)3,4-dihydro[2R-2α,3α,8β,14β,15R] der Formel (I)

Figure 00010001
wurde aus dem Samen von Aesculus hippocastanum (Tetrahedron Lett., 429, 1966) isoliert. In EP-A-210785 (4. Februar 1987) wird die therapeutische Verwendung von Proanthocyanidin A2 als narbenbildendes, Schleimhaut schützendes, Anti-Geschwür-, Venen öffnendes, Gefäß schützendes und Anitperoxidase-Mittel offenbart.Proanthocyanidin A2 or 8,14-methano-2H, 14H-1-benzopyrano [7,8-d] [1,3] benzodioxocin-3,5,11,13,15-pentol-2,8-bis- (3rd , 4-dihydroxyphenyl) 3,4-dihydro [2R-2α, 3α, 8β, 14β, 15R] of the formula (I)
Figure 00010001
was isolated from the seed of Aesculus hippocastanum (Tetrahedron Lett., 429, 1966). EP-A-210785 (February 4, 1987) discloses the therapeutic use of proanthocyanidin A2 as a scar-forming, mucosal protective, anti-ulcer, vein opening, vascular protecting and anti-peroxidase agent.

US 5 648 377 offenbart Formulierungen, die eine Kombination von lipophilen und hydrophilien Antioxidationsmitteln umfaßt, die für die Behandlung von physiopathologischen Zuständen geeignet sind, die auf eine Überproduktion freier Radikale zurückzuführen ist, Atherosklerose eingeschlossen. US 5,648,377 discloses formulations comprising a combination of lipophilic and hydrophilic antioxidants suitable for the treatment of physiopathological conditions due to free radical overproduction, including atherosclerosis.

Proanthocyanidin A2 wird als ein hydrophiles Antioxidationsmittel offenbart, während Phospholipide als oberflächenaktive Stoffe verwendet werden.Proanthocyanidin A2 is considered a hydrophilic antioxidant revealed while phospholipids as surface active Fabrics are used.

Es ist nunmehr überraschend herausgefunden worden, daß die Phospholipidkomplexe von Proanthocyanidin A2 sowohl auf Tiere als auch auf Menschen eine deutlich antiatherosklero tische Wirkung ausüben, wenn sie systemisch, vorzugsweise auf oralem Wege, verabreicht werden.It has now surprisingly been found out been that the Phospholipid complexes of proanthocyanidin A2 both on animals and also have a clearly anti-atherosclerotic effect on humans, if they are administered systemically, preferably orally.

Die Komplexe der Erfindung können aus natürlichen oder synthetischen Phospholipiden bestehen, wie Lezithinen, Phosphatidylcholin, Phosphatidylserin, Phosphatidylethanolamin. Das Verhältnis von Proanthoxyanidin A2 zu den Phospholipiden liegt zwischen 2 : 1 und 1 : 2 und ist vorzugsweise 1 : 1,5 w/w. Ein besonders bevorzugter Komplex ist der mit Soja-Phosphatidylcholin.The complexes of the invention can be derived from natural or synthetic phospholipids, such as lecithins, phosphatidylcholine, Phosphatidylserine, phosphatidylethanolamine. The ratio of Proanthoxyanidin A2 to the phospholipids is between 2: 1 and 1: 2 and is preferably 1: 1.5 w / w. A particularly preferred one The complex is that with soy phosphatidylcholine.

Die Komplexe der Erfindung werden durch die Umsetzung einer Lösung aus dem Phospholipid mit einer Lösung aus Proanthocyanidin A2 in geeigneten Lösungsmitteln, wie Aceton, Ethylacetat, Ethanol, und dem anschließenden Konzentrieren des Reaktionsgemisches unter vermindertem Druck, um einen dicken Rückstand zu erhalten, der gemahlen werden kann, hergestellt.The complexes of the invention will be by implementing a solution from the phospholipid with a solution from proanthocyanidin A2 in suitable solvents, such as acetone, ethyl acetate, Ethanol, and the subsequent Concentrate the reaction mixture under reduced pressure to a big gap to obtain, which can be ground.

Die Komplexe der Erfindung verhindern oder vermindern, in Abhängigkeit der Dosierung die Bildung von atherosklerotischen Plaques. Die Wirkung wurde bewiesen, in dem Kaninchen mit einem Cholesterinspiegel erhöhenden Heilfutter gefüttert wurden, um so atherosklerotische Schädigungen, die denen des Menschen ähneln, beispielsweise im Gefäßbereich, insbesondere dem aortalen Bogen, der ventralen Aorta, Halsschlagadern und cerebralen Gefäßen, hervorzurufen. In dem Model verändern die obengenannten Phospholipidkomplexe den makro- und mikroskopisch vaskulären Zustand was im Vergleich mit unbehandelten Tieren sowohl die Zahl als auch die Heftigkeit der atheromatösen Plaques vermindert, bei gleichzeitig überraschendem Vaskulärgewebe-Nutzen. In einem anderen Atherosklerose-Modell zum Zwecke cerebralen Schutzes, in dem der Gefäßlumen einer Kaninchenarterie operativ verringert worden ist, während ein den Cholesterinspiegel erhöhendes Heilfutter verabreicht wurde, das reich an gesättigten Fetten ist, wurden verminderte Arterienverstopfung, eine Verkleinerung der Gefäßwanddicken und ein erhöhtes Überleben der Tiere beobachtet. Atherosklerose-Patienten zeigten nach einer sechsmonatigen Behandlung verminderte Arterienverstopfung aufgrund von atheromatösen Plaques und einen verbesserten Arterienfluß, was durch die Doppler-Ultrasonography bewertet wurde.Prevent the complexes of the invention or decrease, depending the dosage the formation of atherosclerotic plaques. The effect has been proven in the rabbit with a cholesterol-increasing medicinal feed lined were atherosclerotic lesions similar to those of humans, for example in the vascular area, especially the aortic arch, the ventral aorta, carotid arteries and cerebral vessels. Change in the model the above-mentioned phospholipid complexes the macro and microscopic vascular State what both the number compared to untreated animals as well as the severity of the atheromatous plaques decreased surprising at the same time Vaskulärgewebe benefits. In another atherosclerosis model for cerebral protection, in which the vessel lumen one Rabbit artery has been surgically reduced during one increasing cholesterol Medicinal feed that is rich in saturated fats has been administered reduced artery blockage, a reduction in the thickness of the vessel wall and increased survival watching the animals. Atherosclerosis patients showed up after a six-month period Treatment decreased artery blockage due to atheromatous plaques and improved arterial flow, as evidenced by Doppler ultrasonography was evaluated.

Die Phospholipidkomplexe von Proanthocyanidin A2 können in geeigneten Verabreichungsformen auf oralem Wege, wie Tabletten, Weich- oder Hartgelatinekapseln, in einem Dosierbereich von 50 bis 500 mg zwei bis drei Mal pro Tag in Abhängigkeit der Schwere der Krankheit angewendet werden. Die Herstellung von pharmazeutischen Formulierungen kann gemäß konventioneller Techniken und Trägersubstanzen durchgeführt werden.The phospholipid complexes of proanthocyanidin A2 can be in suitable administration forms orally, such as tablets, soft or hard gelatin capsules, in a dosage range of 50 to 500 mg two to three times a day depending on the severity of the disease. Pharmaceutical formulations can be prepared in accordance with conventional techniques and carriers.

Die folgenden Beispiele veranschaulichen die Erfindung ausführlicher.The following examples illustrate the invention in more detail.

Beispiel 1example 1

Herstellung des Komplexes von Proanthocyanidin A2 mit PhosphatidylcholinProduction of the complex of proanthocyanidin A2 with phosphatidylcholine

Eine Lösung aus 1.577 g Phosphatidylcholin in 51 Ethylacetat, die bei 70°C gehalten wurde, wurde zusammen mit einer Lösung aus 1 kg Proanthocyanidin A2 in 51 Aceton gegeben.A solution of 1,577 g phosphatidylcholine in 51 ethyl acetate at 70 ° C was kept together with a solution of 1 kg of proanthocyanidin A2 given in 51 acetone.

Das Gemisch wurde unter Rühren bis zum Rückfluß gekocht und unter Vakuum bis zur Trockne verdampft. Der Rückstand wurde 24 h bei 50°C unter Vakuum getrocknet und anschließend bis auf die gewünschte Teilchengröße zermahlen.The mixture was stirred until cooked to reflux and evaporated to dryness under vacuum. The residue was 24 h at 50 ° C dried under vacuum and then ground to the desired particle size.

Beispiel 2Example 2

32 Neuseeland-Kaninchen wurden in 4er Gruppen von je 8 Tieren eingeteilt und wie folgt behandelt:
Gruppe 1): Kontrolltier, normales Heilfutter
Gruppe 2): Cholesterinspiegel erhöhendes Heilfutter (0,2% w/w Cholesterin)
Gruppe 3): Cholesterinspiegel erhöhendes Heilfutter + Phospholipidkomplex aus Proanthocyanidin A2-Extrakt (0,2% Cholesterin + 2% w/w Komplex aus Beispiel 1).
Gruppe 4): Cholesterinspiegel erhöhendes Heilfutter + Proanthocyanidin A2-Extrakt (0,2% Cholesterin + die Menge Proanthocyanidin A2, äquivalent der, die in 2% w/w des Komplexes aus Beispiel 1 vorhanden ist).32 New Zealand rabbits were divided into groups of 4, each with 8 animals, and treated as follows:
Group 1): control animal, normal medicinal feed
Group 2): Medicinal feed raising cholesterol levels (0.2% w / w cholesterol)
Group 3): Cholesterol-level medicinal feed + phospholipid complex from proanthocyanidin A2 extract (0.2% cholesterol + 2% w / w complex from example 1).
Group 4): Cholesterol-level medicinal feed + proanthocyanidin A2 extract (0.2% cholesterol + the amount of proanthocyanidin A2, equivalent to that which is present in 2% w / w of the complex from example 1).

Nach achtwöchiger Behandlung, in denen Cholesterin-, LDL/VLDL-, HDL- und Triglyceridspiegel gemessen wurden, wurden die Tiere umgebracht.After eight weeks of treatment in which Cholesterol, LDL / VLDL, HDL and triglyceride levels were measured, the animals were killed.

Die Anzahl, die Größe und die Verteilung der atherosklerotischen Schädigungen an der Brust- und Bauchaorta wurden bewertet.The number, the size and the Distribution of atherosclerotic damage to the chest and abdominal aorta were rated.

Die Aortastreifen wurden befestigt und mit Sudan IV gefärbt, um die Schädigungen sichtbar zu machen und das vasale Cholesterin und den Gehalt an oxidiertem Cholesterin durch Gaschromatographie zu bewerten.The aortic strips were attached and stained with Sudan IV, about the injuries to make visible and the vasal cholesterol and the content of evaluate oxidized cholesterol by gas chromatography.

Die in der folgenden Tabelle angegeben Ergebnisse beweisen, daß die Behandlung mit Phospholipidkomplexen von Proanthocyanidin A2 auf statistisch signifikante Weise die atherosklerotischen Schädigungen vermindern, die durch Cholesterinspiegel erhöhendes Heilfutter hervorgerufen wurden. Tabelle Behandlung Fläche der Schädigung in Prozent Gruppe 1 0,5% Gruppe 2 34% Gruppe 3 7,5% Gruppe 4 30% Beispiel 3 500 mg Phospholipidkomplex aus Proanthocyanidin A2 enthaltende Kapseln Zusammensetzung: Komplex aus Proanthocyanidin A2 mit Sojaphosphatidylcholin 150 mg Lactose 57 mg modifizierte Stärke 40 mg Magnesiumstearat 3,0 mg Beispiel 4 Gastro-resistente Tabletten Komplex aus Proanthocyanidin A2 mit Sojaphosphatidylcholin 200 mg mikrochristalline Cellulose 118 mg gefälltes Siliciumdioxid 3 mg Magnesiumsteatat 4 mg Anionisches Polymer aus Methacrylsäure und Ester hiervon 12 mg Talk 8 mg Magnesiumcarbonat 8 mg Maisstärke 5 mg Gummiarabicum 159 mg Beispiel 5 Weich-Gelatine Kapseln Komplex aus Proanthocyanidin A2 mit Sojaphosphatidylcholin 216 mg Erdnußöl 209 mg teilweise hydrierte Pflanzenöle 100 mg Sojalezithin 5 mg The results shown in the following table demonstrate that treatment with phospholipid complexes of proanthocyanidin A2 statistically significantly reduce the atherosclerotic damage caused by medicinal feed which increases cholesterol levels. table treatment Area of damage in percent Group 1 0.5% Group 2 34% Group 3 7.5% Group 4 30% Example 3 Capsules Containing 500 mg of Phospholipid Complex from Proanthocyanidin A2 Composition: Proanthocyanidin A2 complex with soy phosphatidylcholine 150 mg lactose 57 mg modified starch 40 mg magnesium stearate 3.0 mg Example 4 Gastro-resistant tablets Proanthocyanidin A2 complex with soy phosphatidylcholine 200 mg microchrystalline cellulose 118 mg precipitated silicon dioxide 3 mg Magnesiumsteatat 4 mg Anionic polymer made from methacrylic acid and ester thereof 12 mg talc 8 mg magnesium carbonate 8 mg corn starch 5 mg gum arabic 159 mg Example 5 Soft Gelatin Capsules Proanthocyanidin A2 complex with soy phosphatidylcholine 216 mg Peanut oil 209 mg partially hydrogenated vegetable oils 100 mg soy lecithin 5 mg

Claims (9)

Phospholipidkomplexe von Proanthocyanidin A2.Phospholipid complexes of proanthocyanidin A2. Komplexe nach Anspruch 1, wobei die Phospholipide aus Lecithinen, Phosphatidylcholin, Phosphatidylethanolamin, Phosphatidylserin ausgewählt sind.Complexes according to claim 1, wherein the phospholipids from lecithins, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine selected are. Komplexe nach Anspruch 2, wobei das Phospholipid Phosphatidylcholin ist.Complexes according to claim 2, wherein the phospholipid Is phosphatidylcholine. Komplexe nach einem der Ansprüche 1 bis 3, wobei das Gewichtsverhältnis von Proanthocyanidin A2 zu Phospholipid zwischen 2 : 1 und 1 : 2 liegt.Complexes according to any one of claims 1 to 3, wherein the weight ratio of Proanthocyanidin A2 to phospholipid is between 2: 1 and 1: 2. Verwendung der Komplexe nach den Ansprüchen 1 bis 4 zur Herstellung von Medikamenten für die prophylaktische oder therapeutische Behandlung von Atherosklerose und von Herz- und Hirninfarkt.Use of the complexes according to claims 1 to 4 for the manufacture of medications for prophylactic or therapeutic treatment of atherosclerosis and of heart and brain infarction. Verwendung nach Anspruch 5, wobei die Einheitsdosis des Medikaments zwischen 50 und 500 mg Wirkstoff liegt.Use according to claim 5, wherein the unit dose the drug is between 50 and 500 mg of active ingredient. Verwendung nach Anspruch 5 oder 6, wobei das Medikament auf oralem Weg verabreichbar ist.Use according to claim 5 or 6, wherein the medicament is administered orally. Verwendung nach Anspruch 7, wobei das Medikament in Form von Weich- oder Hartgelatine-Kapseln oder -Tabletten vorliegt.Use according to claim 7, wherein the medicament is in the form of soft or hard gelatin capsules or tablets. Pharmazeutische Zusammensetzungen, enthaltend einen Komplex nach den Ansprüchen 1 bis 4 als Wirkstoff.Pharmaceutical compositions containing one Complex according to the requirements 1 to 4 as an active ingredient.
DE69907509T 1998-12-18 1999-12-13 PPHOSPHOLIPID COMPLEXES OF PROANTHOCYANIDINE A2 AS ANTIATHEROSCLEROTIC AGENTS Expired - Lifetime DE69907509T2 (en)

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IT1998MI002732A IT1304183B1 (en) 1998-12-18 1998-12-18 PROANTOCYANIDINE A2 COMPLEXES WITH PHOSPHOLIPIDES AS AGENTIANTIATEROSCLEROTICI.
ITMI982732 1998-12-18
PCT/EP1999/009854 WO2000037062A2 (en) 1998-12-18 1999-12-13 Phospholipid complexes of proanthocyanidin a2 as antiatherosclerotic agents

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ITMI982732A1 (en) 2000-06-18
WO2000037062A3 (en) 2000-08-03
IL143751A0 (en) 2002-04-21
HUP0104665A3 (en) 2003-01-28
PL197153B1 (en) 2008-03-31
KR20010093826A (en) 2001-10-29
AU763907B2 (en) 2003-08-07
HK1042430A1 (en) 2002-08-16
NO328733B1 (en) 2010-05-03
PT1140115E (en) 2003-08-29
HK1042430B (en) 2004-10-08
EP1140115B1 (en) 2003-05-02
ES2197708T3 (en) 2004-01-01

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